The field of the present invention is the area of medical prostheses, including artificial blood vessels, and materials and methods for coating same so as to improve performance, especially by minimizing thrombosis.
Atherosclerosis is a serious cause of morbidity and mortality despite advances in preventive measures and pharmacological therapeutics. Nearly 700,000 vascular surgical procedures are preformed each year in the United Stats along with several hundred thousand peripheral and coronary angioplasties. Prosthetic bypass grafts and, more recently, arterial stents and other endovascular prosthesis have been utilized in association with these reconstructive procedures. Although large diameter vascular grafts (at least 6 mm internal diameter) have been successfully developed from polymers such as polytetrafluoroethylene (PTFE) and polyethylene terephthalate, the fabrication of a durable small diameter prosthesis (less than 6 mm internal diameter) remains unresolved. Thrombus formation and restenosis currently limit usefulness of small diameter grafts, and these complications require that the patient endure discomfort, health risks and further medical treatments. Furthermore, while prosthetic bypass grafting can be performed in the infrainguinal position with reasonable short term success, within 5 years 30-60% of these grafts fail. Likewise, restenosis and/or occlusion occur in as many as half of all patients within 6 months of stent placement, depending upon the site and the extent of the disease.
It is recognized that the adverse events leading to the failure of many vascular prostheses are related to maladaptive biological reactions at the blood-material and the tissue-material interfaces. In response to these problems, and particularly thrombosis of the small caliber prosthesis, grafts and stents have been coated with albumin, heparin and prostacyclin analogs, which inhibit the clotting cascade and platelet reactivity, or with relatively inert materials, such as polyethylene oxide. An alternate approach has been to design materials which support the in situ regeneration of an endothelial cell line in order to create a functional arterial substitute with a durable thromboresistant interface. However, strategies based on the coating or derivitization of fr a prosthetic have not overcome the capacity of these same substrates to activate platelets and the coagulation cascade. Thus, in the period prior to complete endothelial regeneration, the surface of a small diameter prosthesis remains at increased risk for thrombus formation. Notwithstanding the recognized difficulties of this approach, including the additional constraints for both selective cell growth and normal endothelial function, a biohybrid strategy does offer the potential for incorporating into a prosthesis at least some of the complex physiological response which nature appears to require in this environment.
The control of thrombus formation on molecularly engineered surfaces is critical in the development of improved small diameter arterial prostheses for use in cardiac, plastic and vascular surgery, as well as in the successful implantation of artificial organs and metabolic support systems. It has been postulated that a clinically durable vascular prosthesis may be achieved by identifying and incorporating actively antithrombogenic mechanisms that operate at the blood-material interface under a range of hemodynamic conditions.
Previous attempts to create antithrombogenic materials have includes those where thrombomodulin was attached to artificial materials including polyethylene, acryloyl-modified polytetrafluoroethylene, poly acrylic-acid modified polyethylene, and cellulosic materials (See. e.g., Kishida et al. (1994) Biomaterials 15(10):848-852; Kishida et al. (1994) Biomaterials 15(14): 1170-1174; Kishida et al. (1994) ASAIO Journal 40(3):M840-845; Vasilets et al. (1997) Biomaterials 18(17):1139-1145; Kishida et al. (1995) ASAIO Journal 41:M369-374).
There is a longfelt need in the art for a clinically durable small diameter vascular prosthesis so that graft performance is improved, especially with respect to thrombus formation and restenosis associated with the small diameter grafts, with concomitant improvement in patient outcomes and quality of life and in the economic costs of surgical procedures involving implant of prosthetic blood vessels and other prosthetic materials.